This invention relates to polymeric material, for example, coatings, films and gels, especially pharmaceutically acceptable bioadhesive coatings, films and gels and more specifically to improved methods for producing such coatings, films and gels.
Many polymers are known to be bioadhesive (i.e. able to adhere to biological surfaces, e.g. mucus, the skin, mucosal surfaces, epithelium etc.) and the value of this property is well recognised. For example, bioadhesives may be used to adhere active agents to specific sites in the body for local drug administration, or to coat particular parts of the body. However, when bioadhesives are applied to such surfaces in aqueous solution they may be easily washed off or mechanically removed, because the strength of adhesion of each individual bioadhesive molecule to the surface is not very high. This may lead to further problems if the bioadhesive materials contain active agents intended for use at one particular site, but which are washed away to other sites.
Thus to improve the retention of bioadhesives at a surface they may be formed into films. Such films may be formed either by chemical crosslinking or by physical interaction of the bioadhesive molecules as they come out of solution. However, all of the known methods of film formation have drawbacks with regard to their use at biological surfaces. For example, if bioadhesive films are formed before being applied to a surface (e.g. by weaving polymer strands or by slow evaporation of aqueous solutions of the polymers) they will be awkward to apply to relatively inaccessible parts of the body (e.g. the back of the throat or the underside of the tongue); furthermore, for a number of biopolymers, much of the bioadhesive character of the films may be lost if they become too dry.
Alternatively, current methods for forming bioadhesive films directly on a surface require the use of volatile solvents, which quickly evaporate to leave a film, but which are not suitable for use on sensitive areas of a body (e.g. open wounds, mucosal surfaces, etc.).
A need exists for coatings, gels and/or films, especially bioadhesive coatings, gels and films, capable of being formed directly on surfaces which avoids the use of volatile solvents.
A further need exists for a formulation which is capable of forming a bioadhesive coating, film or gel in situ and which may be provided to the consumer in stable form in a single dosage form containing both components.
According to the invention there is provided a pharmaceutically acceptable polymeric material formed in situ at a body surface, wherein the material is formed by the reaction of:
i) an anionic polymer or tripolyphosphate (component a); and
ii) a cationic polymer (component b) in the presence of water.
Further according to the invention there is provided a process for the preparation of a pharmaceutically acceptable polymeric material in situ at a body surface by applying
i) an anionic polymer or tripolyphosphate (component a) and;
ii) a cationic polymer (component b)
to the body surface wherein component a) is capable of reacting with component b) to form the polymeric material.
Preferably the polymeric material is a bioadhesive coating, film or gel.
Preferably, the polymers are applied sequentially and the first applied polymer is a bioadhesive polymer.
Preferably component a) has one or more acid (proton donor) groups, for example xe2x80x94COOH and/or xe2x80x94SO3H.
Preferably component b) has one or more basic (proton acceptor) groups, for example xe2x80x94NH2 and/or NHCH3.
Component a) may be selected from any anionic polymers that are water-soluble or dispersible and that will form a coating, gel or film in the presence of component b). Preferred anionic polymers include water-soluble salts of hyaluronic acid, water-soluble salts of alginic acids (e.g. sodium alginate, potassium alginate), water-soluble or dispersible salts of polyacrylic acids (e.g. sodium carbomers), xanthan gum, acacia, pectins, sterculia, carrageenan salts, polylactic acid and water-soluble cellulose derivatives (e.g.sodium carboxymethyl cellulose). Most preferred anionic polymers for use in the present invention are water soluble or dispersible carbomer salts, water-soluble salts of alginic acids and water-soluble salts of cellulose derivatives.
Mixtures of anionic polymers may be used, as long as they do not themselves crosslink to form films until component b) is added to them.
The concentration of component a) in the the bioadhesive coating, gels or films of the invention will depend upon a number of factors (e.g. the strength of the film, gel or coating to be produced, the solubility of the polymers, the required viscosity of the solution etc.). Generally the concentration will preferably be selected from the range 0.1 to 75% weight to volume (w/v), more preferably 0.5 to 25% w/v based on the composition as a whole.
Component b) may be selected from any cationic polymers that are water-soluble or dispersible and that will form a coating, film or gel in the presence of component a). Preferred cationic polymers include water-soluble chitosan salts (e.g. chitosan chloride, chitosan acetate), polylysine, chondroitin salts, diethylaminoethyl dextran and keratin.
Mixtures of component b) may be used to form the bioadhesive films of the invention, as long as they do not interact to form a film themselves until they have been added component a).
The total amount of component b) in the bioadhesive coatings, films or gels of the invention will depend upon a number of factors including the amount of component a) used, the strength of film required, the effectiveness of component b), etc. Generally the concentration will be selected from 0.1 to 75% w/v, more preferably 0.5 to 25% w/v of the composition as a whole.
The preferred amount may be easily determined by simple experimentation, however the total weight ratio of component a) to component b) will generally be from 1:10 to 10:1, more preferably 1:2 to 2:1.
The balance of the coating, film or gel may be water, any other pharmaceutically effective carriers, fillers and/or excipients.
Where component a) is a water-soluble alginate salt, component b) is preferably selected from water-soluble chitosan salts; diethylaminoethyl dextran and chondroitin sulphate; most preferably a water-soluble chitosan salt.
Where component a) is a water-soluble or dispersible carbomer salt, component b) is preferably selected from water-soluble chitosan salts; diethylaminoethyl dextran and chondroitin sulphate; most preferably a water-soluble chitosan salt.
Where component a) is sodium carboxymethyl cellulose, component b) is preferably a water-soluble chitosan salt.
The bioadhesive coatings, films or gels of the invention may optionally further comprise one or more pharmaceutically active agents, for either local or systematic delivery depending upon the site of application of the coating, film or gel.
Suitable active agents for use in such coatings, films or gels of the invention include analgesics, anti-inflammatory agents and antipyretics (e.g. acetaminophen, ibuprofen, naproxen, diclofenac, ketoprofen, choline salicylate, benzydamine, buprenorphine, hydrocortisone, betamethasone); decongestants (e.g. pseudoephedrine, phenylephrine, oxymetazoline, xylometazoline); mineral salts (e.g. zinc gluconate, zinc acetate); cough suppressants (e.g. dextromethorphan, codeine, pholcodine); expectorants (e.g. guaiphenesin, n-acetylcysteine, bromhexine); antiseptics (e.g. triclosan, chloroxylenol, cetylpyridinium chloride, benzalkonium chloride, amylmetacresol, hexylresorcinol, dichlorobenzyl alcohol, benzyl alcohol, dequalinium chloride, silver sulphadiazine); cardiovascular agents (e.g. glyceryl trinitrate); local anaesthetics (e.g. lignocaine, benzocaine); cytoprotectants (e.g. carbenoxolone, sucralfate, bismuth subsalicylate); antiulcer agents (e.g. calcium carbonate, sodium bicarbonate, magnesium trisilicate, magaldrate, cimetidine, ranitidine, nizatidine, famotidine, omeprazole, pantoprazole); antihistamines (e.g. loratidine, terfenadine, diphenhydramine, chlorphenhydramine, triprolidine, acrivastine); antinausea agents (e.g. prochlorperazine, sumatriptan), bowel regulatory agents (e.g. diphenoxylate, loperamide, sennosides); antifungal agents (e.g. clotrimazole); antibiotics (e.g. fusafungine, tyrothricin) and antipsoriasis agents (e.g. dithranol, calcipotriol).
Mixtures of the active agents may be included in the coatings, films or gels of the invention where appropriate.
The active agents may be contained in either of components a) and b) before they are applied to the body surface, but most preferably they are contained in component a).
The concentrations of the active agents will depend upon their standard dosages and whether they are for local or systemic release etc. Generally the suitable concentrations will be readily apparent to one skilled in the art of formulation (normally a concentration range of 0.001 to 10% w/v).
Components a) and b) may optionally contain other suitable excipients depending upon the proposed site of application. Examples of suitable excipients include colours, pH adjusters, flavours, sweeteners, preservatives, suspending agents or plasticisers. The concentrations of such excipients will be readily apparent to one skilled in the art of formulation (although they will normally be used in a concentration range of 0.001 to 10% w/v).
In a first aspect of the present invention components a) and b) are present in aqueous solution.
For the purpose of this invention aqueous solutions of components a) or b) also include aqueous dispersions of said materials.
As hereinbefore described, the aqueous solution of component b) may be applied sequentially in any order or simultaneously with the aqueous solution of component a) but more preferably, the aqueous solution of component b) is applied after the aqueous solution of component a).
The amount of time between the application of the two aqueous solutions may vary depending upon the site of application. For example, where component a) applied first is a biopolymer for use in the throat, the two aqueous solutions should be applied within about 10 seconds of each other. In contrast, on a relatively dry, stable surface such as the arm the aqueous solution which is to be applied second may be applied at any time within 5 minutes of the application of the solution applied initially.
It will be clear that the aqueous solution of component a) and the aqueous solution of component b) must be kept apart until they are combined as they are applied to the body surface.
The aqueous solutions of component a) and component b) may be applied to a surface by any suitable means, depending upon the nature and accessibility of the surface. For example, where the surface is a relatively large area that may be suitably positioned (e.g. the back of a hand, etc.) the solutions may be poured on. The solutions may also be applied by use of a dropper (e.g. an eye dropper); or they may be painted on by use of a brush, although care must be taken not to dip the same brush into the component a) solution and then the component b) solution. Alternatively, the solutions may be dispersed from a double-chambered tube, or a double-barrelled syringe. Where the film is intended to be formed in the oesophagus, the aqueous solutions may be applied by being drunk sequentially.
More preferably, the aqueous solutions of component a) and component b) may be sprayed onto the surface.
Any conventional spraying devices may be used for spraying the individual solutions, for example aerosol sprays, pump sprays or trigger sprays. Most preferably, the spray device will be a pump spray or a trigger spray.
Optionally, the two aqueous solutions may be applied by different means, for example the aqueous solution containing component a) may be painted on and the aqueous solution containing component b) may be sprayed on.
When an aqueous solution of component a) is applied to a surface and an aqueous solution of component b) is applied shortly thereafter (according to a preferred embodiment of this aspect of the invention) only that portion of component a) which comes into contact with component b) will react to form a film. Thus a proportion of component a) (especially that in closest proximity to the surface) may not simply form a film but may be coated by the film formed above it. The film in this case is effectively a coating which can thus encapsulate the unreacted component a) and help to prevent it being removed. Thus the film will coat a reservoir of substantially unreacted component a) in this case. This effect will be most pronounced when the two aqueous solutions are sprayed onto the surface, because the droplets so formed will have the most suitable shape to maximise the encapsulation effect.
In a most preferred embodiment of this aspect of the invention there is provided a process for the preparation of a pharmaceutically acceptable polymeric in situ at a body surface, the polymeric material coating a reservoir of substantially unreacted component a) and holding it in close proximity to the body surface, comprising the steps of applying an aqueous solution of component a) onto the body surface and subsequently applying an aqueous solution of component b) onto the same surface. The method of application is preferably spraying.
Preferably the polymeric material is a bioadhesive coating, film or gel.
In this embodiment, component a) is preferably a bioadhesive polymer, most preferably a water-soluble alginate salt and component b) is most preferably a water-soluble chitosan salt. Optionally, the aqueous solution of component a) also comprises an active agent so that a reservoir containing some of the active ingredient may be formed in close proximity to the surface.
Further according to this first aspect of the present invention, there is provided the use of:
i) an anionic polymer or tripolyphosphate (component a); and
ii) a cationic polymer (component b)
(and optionally one or more active agents) for the preparation of aqueous solutions for application to a body surface to form a pharmaceutically acceptable polymeric material thereon wherein component a) is capable of reacting with component b) to form the material.
Preferably the polymeric material is a bioadhesive coating, film or gel.
Preferably the coating includes a reservoir of substantially unreacted component a).
Optionally, the reservoir of unreacted component a) further comprises one or more active agents such as those exemplified above.
Still further according to this first aspect of the present invention there is provided a pharmaceutical pack comprising:
i) an aqueous solution of an anionic polymer or tripolyphosphate (component a); and
ii) an aqueous solution of a cationic polymer (component b)
wherein component a) is capable of reacting with component b) to form a pharmaceutically acceptable polymeric material in situ at a body surface and the pack is suitable for applying the two solutions to the body surface such that the polymeric material is formed at that surface.
Preferably the polymeric material is a bioadhesive coating, film or gel.
The pharmaceutical pack may comprise two discrete containers, one for each aqueous solution; but preferably the pack will comprise two containers which are joined together; or, most preferably, the pharmaceutical pack will comprise a single container having separate compartments for each aqueous solution.
Where the pharmaceutical pack is a single container it may have separate dispensing means for each solution. For example, there may be spray dispensing means fitted at each end of the container (or next to each other) to provide sequential spraying of the two aqueous solutions.
Alternatively, in a preferred embodiment, the pharmaceutical pack comprises a single dispensing means which is most preferably a spray-dispensing means. The dispensing means may be adjusted to either dispense both aqueous solutions simultaneously, or, more preferably, to dispense them sequentially, either by single or multiple activations of the dispensing means.
Still further according to this first aspect of the invention, there is provided the use of a process as described above in therapy, and in particular for the treatment of diseases of the throat and mouth.
Still further according to this first aspect of the invention, there is provided the use of a process as described above for the preparation of a medicament for the treatment of disorders of the upper GI tract.
In a second aspect to the present invention, there is provided a non-aqueous formulation for forming a pharmaceutically acceptable polymeric material in situ at a body surface, the formulation including
i) an anionic polymer or tripolyphosphate (component a);
ii) a cationic polymer (component b); and
iii) optionally a pharmaceutically acceptable inert filler or carrier
wherein component a) is capable of reacting with component b) to form the polymeric material in situ following application to or ingestion by a mammal.
Preferably the polymeric material is a bioadhesive coating, film or gel.
The formulation may be liquid or solid.
The pharmaceutically acceptable inert filler or carrier of the invention may include a glycol, for example propylene glycol, a medium chain triglyceride oil, for example, Miglyol (RTM) (Huls Chemicals), a glyceride, for example Transcutol (RTM) (Gattefosse) and/or mannitol.
The formulation of this aspect of the present invention may optionally include one or more active agents, for either local or systemic delivery depending upon the site of application of the film. In the case of delivery to the mouth, for example, active agents may be included to provide a local effect such as an analgesic or antiseptic action and/or to provide a systemic effect (for example, an anti-histamine or an anti-nausea agent).
Suitable active agents for use in such films or gels of the invention are as described above.
Mixtures of active agents may be included in the formulation of the invention, where appropriate.
In addition, the formulations of the present invention may optionally contain other suitable excipients depending upon the proposed site and/or mode of application. Examples of suitable excipients are as described above with the inclusion of granulating agents such as polyvinyl pyrrolidone, and/or magnesium stearate.
Preferably, the mammal is a human although it will be appreciated that the present invention can have application in animals.
The present invention thus provides formulations which can be used for preparing pharmaceutically acceptable bioadhesive coatings, gels and films in situ. Unexpectedly, some of the films formed by this process also have improved properties such as strength and adhesion as a result of their targeted delivery.
In one embodiment of this second aspect to the present invention, the formulation is presented as a non-aqueous liquid formulation in which both component a) and component b) are dispersed or suspended.
Such a formulation may be taken orally by drinking or pouring, or by spraying.
Alternatively, in another embodiment of this second aspect to the present invention, the formulation may be in the form of a dry powder which contains components a) and b) (and optionally c)) as an intimate mixture. The powder is suitable for delivery to the mouth or throat via an inhaler. The powder granules, which are of a size of more than 10xcexcm, provide a coating in the mouth or on the throat by absorbing water so that component a) and component b) may react to form a bioadhesive film.
Equally, in another embodiment of this second aspect the formulation may be presented in the form of a tablet or lozenge containing both components necessary to form a bioadhesive film. The tablet or lozenge may be bi-layered, in which case, component a) may be present in one half and component b) may be present in the other half. Alternatively, these components could be presented as an intimate mixture.
On ingestion of the tablet, salivation allows release and dissolution of component a) and component b) so that reaction occurs between them to form a bioadhesive film or a gelatinous mass.
Another embodiment of this second aspect to the present invention relates to a formulation which employs a controlled-release capsule containing both component a) and component b) within a hard or soft capsule. The capsule is made from gelatin or a suitable equivalent and opens in the stomach to allow reaction of components a) and b) to form a bioadhesive film or a gelatinous mass.
The novel formulations of the present invention are all one-component non-aqueous systems containing both component a) and component b). In situ, water which is present at (or which may be provided at) the delivery site is absorbed by the formulation, thereby enabling component a) and component b) to react to form a bioadhesive film or a gel.
It will be appreciated by those skilled in the art that component a) and b) will not crosslink to form a bioadhesive coating, film or gel unless in an aqueous environment. Significant advantages accrue from keeping components a) and b) in a non-aqueous (and therefore non-crosslinking) environment, particularly insofar as the two components may be stored together without reacting therefore allowing simultaneous (and therefore quicker) application to a location in a single dosage form.
Components a) and b) may be applied to the surface by any suitable means, depending upon the nature and accessibility of the surface and on the nature of formulation which is appropriate for delivery to the surface. For example, where the surface is a relatively large area that may be suitably positioned (e.g. an external surface such as the back of a hand, etc.) a liquid formulation may be poured on, or may be applied by use of a dropper (e.g. an eye dropper), or may be painted on by use of a brush, or may be dispersed from a syringe. Where the film is intended to be formed in the oesophagus, the film could be produced by drinking a liquid formulation or by the ingestion of a tablet or capsule formulation. When the film is to be formed on the back of the throat or in the nasal cavity, the dry powder formulation may be the most appropriate to ensure accurate delivery and film formation.
Any conventional spraying devices may be used for spraying the liquid formulation, for example aerosol sprays, pump sprays or trigger sprays.
Most preferably the spray device will be a pump spray or a trigger spray.
Further according to this second aspect of the present invention, there is provided the use of the above formulation in therapy, and in particular for the treatment of diseases of the throat and mouth.
Further according to this aspect of the present invention, there is also provided the use of the above formulation for the preparation of a medicament for the treatment of disorders of the upper GI tract.
The bioadhesive coatings, films or gels according to the invention in this case may act as a barrier to prevent further damage/contamination to wounded areas of skin (e.g. wounds, or sites of eczema etc.), to soothe sore areas of the body (e.g. sore throats etc.); or as systemic drug delivery films (e.g. transdermal films on intact skin, sublingual delivery films on the underside of the tongue etc.). Such coatings, films or gels are particularly useful for local delivery of active agents, as they prevent the active agents from being washed away from the site of application, i.e. they minimise the effect of the active agent on the surrounding tissue (e.g. a topical anaesthetic in the throat).
The bioadhesive coatings, films or gels of the invention may be formed upon any surface of the mammalian body as required. Suitable surfaces include any region of the skin (for example to cover a wound or act as a drug delivery patch), the back of the throat or the oesophagus (e.g. to provide mechanical protection/soothing, or to deliver active agents locally or systematically); the underside of the tongue (as a sublingual dosage form the systemic delivery) or in the nasal cavity, vagina or rectum (as local drug delivery forms).